There is considerable interest in developing nanohybrids of imaging contrast agents and drugs for image-guided drug delivery. We have developed a strategy of utilizing manganese (Mn) to enhance the nano-encapsulation of arsenic trioxide (ATO). Formation of arsenite (As<sup>3+</sup>)-Mn precipitates in liposomes generates magnetic susceptibility effects, reflected as dark contrast on T<inf>2</inf>-weighted MRI. Intriguingly, following cell uptake, the As-Mn complex decomposes in response to low pH in endosome-lysosome releasing ionic As<sup>3+</sup>, the active form of ATO, and Mn<sup>2+</sup>, the T<inf>1</inf> contrast agent that gives a bright signal. Glioblastoma (GBM) is well known for its high resistance to chemotherapy, e.g., temozolomide (TMZ). Building upon the previously established phosphatidylserine (PS)-targeted nanoplatform that has excellent GBM-targeting specificity, we now demonstrate the effectiveness of the targeted nanoformulated ATO for treating TMZ-resistant GBM cells and the ability of the convertible Mn contrast as a surrogate revealing the delivery and release of ATO.
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